Fluorine substitution is a powerful tool to improve the bioavailability of pharmaceuticals and agrochemicals. Thus, an expansive set of nucleophilic and electrophilic reagents have been developed to replace various C—X functional groups with C—F.    [CheMBioChem Special Issue: Fluorine In the Life Sciences 2004, 5, 557726]. Simplest among the nucleophilic fluorinating reagents are “anhydrous” or “naked” organic fluoride salts, represented by tetramethylammonium fluoride (TMAF) [Christe, K. O, et al, J. Am. Chem. Soc. 1990, 112, 7619-25, 1-methylhexamethylenetetramine fluoride (MHAF) [Gnann, R. Z., et al, J. Am. Chem. Soc. 1997, 119, 112-115] and tetramethylphosphonium fluoride (TMPF) [Kornath, A, et al, Inorg. Chem. 2003, 42, 2894-2901]. Highly soluble anhydrous fluoride salts possessing a wide variety of alkyl groups are desirable for synthetic purposes, but these compounds cannot be prepared according to current methodologies.
Typical of prior art methods for preparing such salts are those described in U.S. Pat. No. 5,369,212 and Canadian patent no. 2035561.
The preparation of absolutely anhydrous fluoride salts whose cations are substituted with alkyl groups possessing beta-hydrogen atoms has proved to be a significant challenge. Approximately 20 years ago, the first claims for “anhydrous” tetrabutylammonium fluoride appeared. The compounds were prepared by physical drying of the hydrated salt, i.e., dynamic high vacuum (<0.1 mmHg) to remove water for at least 48 hours from TBAF·3H2O at 40˜45° C. (JOC, 1984, 49, 3216-3219). However, there was still 0.1 to 0.3 equiv of water in this “anhydrous” TBAF and copius quantities of the elimination products (tributylamine, bifluoride ion, and butane) as a result of this process. The side reactions and the presence of water and tributylamine significantly decrease the reactivity of the fluoride ion and lead to significant side reactions, such as hydrolysis of the starting substrates. An example of water's deleterious effects upon the reactivity of TBAF can be seen in simple model reactions. For example, if TBAF that is dried using physical methods is combined with benzyl chloride or benzyl bromide at room temperature to 40° C., formation of benzyl fluoride required 8 to 12 hours. In comparison, if truly anhydrous TBAF were employed, the same reaction would only take a few minutes or less at low temperatures and give quantitative yields.
Later, individual syntheses of tetramethylammonium fluoride (TMAF) (JACS, 1990, 112, 7619-7625), cobaltocenium fluoride (Cp2CoF), (JACS, 1994, 116, 11165-11166), 1-Methylhexamethylenetetramine fluoride (MHAF) (JACS, 1997, 119, 112-115), tetramethylphosphonium fluoride (TMPF) (Inorg. Chem., 2003, 42, 2894-2901) as well as several others were synthesized and characterized as “naked” or “anhydrous” fluoride salts. However, each of these salts has specific drawbacks in terms of solubility or reactivity, and the preparative methods for synthesizing these individual salts are not applicable for the preparation of a wide variety of fluoride salts. Anhydrous fluoride salts with alkyl groups capable of beta-elimination (ethyl, propyl, butyl, isopropyl, pentyl, isobutyl, etc.) in particular are not accessible by current methods.
Generally, then, these compounds are commonly prepared in a hydrated state and are subsequently dried by heating under dynamic vacuum or by azeotropic distillation. However, the conditions used to dry these salts are often incompatible with a variety of desirable cations. For example, dried tetrabutylammonium fluoride, (TBAF) [Cox, D. P., et al, J. Org. Chem. 1984, 49, 3216-19] is reported to decompose by Hofmann elimination at room temperature. The salt isolated after dehydration is contaminated with copious amounts of bifluoride ion (HF2) and tributylamine [Shannn, R. K., et al, J. Org. Chem. 1983, 48, 2112-14]. These considerations and findings have led to the belief among those skilled in the art that “it is very unlikely that pure, anhydrous tetraalkylammonium fluoride salts have ever, in fact, been produced in the case of ammonium ions susceptible to E2 eliminations” [Sharma et al, supra].
It is an object of the present invention to provide a novel method of producing truly anhydrous organic fluoride salts and reagents.
It is a further object of the invention to provide novel anhydrous organic fluoride salts and reagents.